Among the most intractable pregnancy pathologies are those related to aberrant trophoblast invasion and the subsequent remodeling of maternal vasculature at the utero-placental interface (UPI). These include preeclampsia (PE), intrauterine growth restriction (IUGR) and abnormally invasive placenta (AIP, aka placenta accreta). Despite this, tools to measure placental structure and function in the crucial late first to early second trimester period have yet to be developed that can be translated from the research environment to routine clinical use. We are now constructing 3D power Doppler ultrasound technologies that provide real-time, quantitative assessment of placental structural and vascular development. We have developed novel semi- automated methods for calculation of placental volume (PlaV) and new methods to measure gross placental morphology (GPM; dimensions, surface area etc.) and to assess the vasculature at the UPI (Fractional Moving Blood Volume, FMBV). We propose four Aims intended to move the field towards routine imaging of placental structure and function in real time and to generate clinically useful tests for monitoring significant placental pathologies. In Aim 1, using machine learning techniques and an extant database of ~2800 1st trimester placental scans, we will fully automate the novel tools developed for measurement of PlaV into a real-time analytical package. Aim 2 will focus on 3D ultrasound techniques to interrogate the vasculature at the UPI through refinement of our new method for determining FMBV, a quantitative measure of vascularity. This will lead to a tool that can assess the entire UPI, a major site of pathology in PE, IUGR and AIP. We also aim to develop 3D power Doppler ultrasound tools for the examination of the size and distribution of the spiral artery jets feeding the intervillous space, enabling us to explore normal and pathological development of the intervillous supply in real-time. Aims 3 and 4 are prospective validation studies designed to test the utility of the tools described above. Aim 3 extends our recently published study of over-invasion of the maternal vasculature to the 1 /2 trimester. The presence and severity of AIP is assessed using Acon, the largest area of standard 3D power Doppler signal at the UPI. Under-invasion will be addressed via analysis of prospectively collected 11-13 week 3D-PD scans in women who develop PE. We will compare PlaV, GPM, FMBV and spiral artery jets in normotensive and preeclamptic pregnancies. The prospective study in Aim 4 will address the environmental impact of smoking by comparing structural and vascular parameters between smokers and non-smokers at weekly intervals from 8-18 wks. These powerful longitudinal studies will map the development of morphologic and vascular features in smokers and non-smokers and provide new insights into the factors responsible for smoking-induced growth restriction. The strong investigative team, composed of bioengineers, maternal-fetal medicine specialists and placental biologists, is delivering these new tools in the research setting and is poised to generate new methods for clinical measurement of placental structure and vascular function in real-time.